The present invention relates to dosage forms for controlled onset and sustained release of active ingredients for human or animal use.
The goal of any drug delivery system is to provide an effective therapeutic amount of a drug to a targeted site in the body to obtain quickly, and then maintain, the desired drug concentration. The two most important aspects of drug delivery are spatial placement and temporal delivery of a drug. Spatial placement relates to the targeting of a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue.
Sustained release drug delivery systems are designed in an attempt to satisfy the spatial placement and temporal delivery of a drug. Sustained release drug delivery systems include any drug delivery system that achieves slow release of a drug over an extended period of time. If these sustained release drug delivery systems can provide some control of drug release in the body, whether this be of a temporal or spatial nature, or both, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered to be a controlled release drug delivery system.
Some therapeutic programs require that the dose of a drug be administered in a time varying pattern of delivery such as a drug free interval followed by a sustained release of the drug for an extended period of time. The science of chronotherapeutics relies on the practice of delivering an effective therapeutic amount of a drug to the desired site of action at the most appropriate time period for a particular disease condition. For example, the greatest incidence of cardiovascular disorders including angina, stroke, heart attack, etc., typically occur during the early morning hours when blood pressure is rising in response to an animal""s natural circadian rhythm. This rise in blood pressure, which occurs at waking, requires a dosage form that is administered upon retiring which dosage form delivers its drug before waking but after a drug free interval during sleep. This time varying pattern or controlled onset of drug delivery provides the required therapy at the appropriate time, thereby substantially lessening the instance of a waking elevated blood pressure.
It is well known in the prior art to provide dosage forms that deliver their contents at a desired rate after a predetermined time delay. Applicant is aware of two such controlled onset and sustained release drug delivery systems currently on the market namely, Verelan(copyright) PM by Schwarz Pharma and Covera-HS(trademark) by G.D. Searle and Co. Verelan(copyright) PM is a verapamil hydrochloride capsule formulation utilizing the proprietary CODAS(trademark) (Chronotherapeutic Oral Drug Absorption System) technology, developed by Elan Corporation PLC and which technology is based on U.S. Pat. No. 4,863,742. U.S. Pat. No. 4,863,742 relates to a controlled absorption verapamil containing pellet formulation for oral administration comprising: (i) a core of (a) a powder mixture containing verapamil or a salt thereof and an organic acid, and (b) a polymeric material containing a major proportion of a water soluble polymer and a minor proportion of a water insoluble polymer, the core comprising layers of the powder mixture and the polymeric material superimposed one upon the other; and (ii) a multi-layer membrane surrounding the core and containing a major proportion of a film-forming, water insoluble polymer and a minor proportion of a film forming water soluble polymer; the release of the verapamil from the pellet being substantially independent of pH and at a rate allowing controlled absorption thereof over a 24 hour period following oral administration.
The individual pellets formulated according to U.S. Pat. No. 4,863,742 may be filled into hard or soft gelatin capsules or may be compressed into tablets. The pellets in the formulation may consist of a blend of pellets formulated to provide various release rates of verapamil. Upon ingestion, the hard or soft gelatin capsules dissolve immediately, thus releasing the individual pellets into the gastrointestinal tract. Likewise, upon ingestion, the compressed tablets are designed to fall apart immediately, thus releasing the individual pellets into the gastrointestinal tract.
The Verelan(copyright) PM capsule formulation, which is based on the teachings of U.S. Pat. No. 4,863,742, is a controlled onset sustained release drug delivery system designed for bed time administration, which incorporates a 4 to 5 hour delay in drug delivery. The Verelan(copyright) PM capsule formulation initiates the release of verapamil hydrochloride 4 to 5 hours after ingestion and results in a maximum plasma concentration (Cmax) of verapamil hydrochloride in the morning hours. The pellet filled, hard gelatin capsules provide for extended release of verapamil hydrochloride in the gastrointestinal tract. The delay is introduced by the level of non-enteric release controlling polymer applied to the verapamil hydrochloride loaded beads. The release controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the verapamil hydrochloride diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the verapamil hydrochloride. The rate of release is essentially independent of pH, posture, and gastrointestinal motility in fed or fasting conditions.
The formulation disclosed in U.S. Pat. No. 4,863,742 and thus the currently marketed Verelan(copyright) PM capsule formulation, has several limitations. In the acidic environment of the stomach (pH 1 to 3) where the verapamil is water soluble, the gastric fluid diffuses through the permeable membrane of each pellet, dissolves the verapamil, and diffuses out through the permeable membrane of each pellet with the dissolved verapamil. The purpose of the organic acid is purportedly to maintain an acidic micro-environment in the pellet core to keep the verapamil soluble, even when the pellet is introduced into the alkaline environment of the lower gastrointestinal tract. Thus, when the pellets descend through the stomach into the alkaline environment of the lower gastrointestinal tract (pH 5 to 7), the verapamil purportedly continues to be dissolved because of the purported continued presence of the organic acid in the core which organic acid maintains the acidity of the micro-environment (assuming the acid has not diffused out). Fluid entering the pellet from the lower gastrointestinal tract (even though more basic) is purportedly neutralized by the presence of the organic acid and the relatively low pH maintained so that the verapamil can purportedly remain in its more soluble state in the maintained acidic micro-environment. Thus, the verapamil purportedly continues to dissolve and diffuse through the multi-layer permeable membrane into the lower gastrointestinal tract.
The difficulty of the approach used in the formulation disclosed in U.S. Pat. No. 4,863,742 and thus the approach used in the Verelan(copyright) PM capsule formulation, is two-fold. Firstly, the organic acid is soluble. Therefore, the organic acid dissolves and diffuses out from the core through the multi-layer permeable membrane as the pellets pass through the gastrointestinal tract. Secondly, the organic acid is subject to neutralization as a result of its contact with the alkaline environment of the lower gastrointestinal tract, where the effectiveness of the organic acid is most needed. At the time when only a percentage of the original amount of verapamil is present in the core, there is a stronger need for solubilization because the less product inside the core, the higher the osmotic pressure needed to permit the verapamil to be pushed out. However, at that point, the quantity of organic acid has had time to diffuse out and another quantity of organic acid has had time to be neutralized. Thus, the organic acid concentration is lower and the system loses its ability to adequately acidify the micro-environment within the pellet surrounded by the multi-layer permeable membrane, becoming less effective when it is more and more needed. As a result of this phenomena, the pellets formulated in accordance with U.S. Pat. No. 4,863,742 and thus the Verelan(copyright) PM capsule formulation does not reliably release verapamil at a sustained rate.
Covera-HS(trademark) is a verapamil hydrochloride tablet formulation utilizing the proprietary OROS(copyright) (Oral Osmotic) technology developed by Alza Corporation and which technology is based on U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338. U.S. Pat. No. 5,160,744 relates to a dosage form for the delayed-delivery of a drug, wherein the dosage form comprises: (a) a first composition comprising the drug verapamil and a poly(ethylene oxide), said poly(ethylene oxide) comprising means for changing from a nondispensable viscosity to a dispensable viscosity when contacted by fluid that enters the dosage form; (b) a second composition comprising a polymeric composition that imbibes fluid and expands, whereby the second composition pushes the first composition from the dosage form; (c) a wall that surrounds the first and second compositions, said wall permeable to the passage of fluid present in the environment of use and comprises a polymeric composition that hydrates slowly when contacted by fluid that enters the wall; (d) at least one exit mans in the wall for delivering the drug from the dosage form; and, wherein the dosage form is characterized by: (e) a delayed-drug interval for delivering verapamil up to 4.5 hours provided by (a), (b) and (c) operating in combination as a unit to provide the delayed-drug interval.
U.S. Pat. Nos. 5,190,765 and 5,252,338 relate to a dosage form for the delayed-delivery of a drug to a fluid environment of use, wherein the dosage form comprises: (a) drug composition comprising a calcium channel blocker drug, and a polymer comprising a molecular weight up to 1,000,000 and a rate of hydration in the presence of fluid that enters the dosage form to change from a non-dispensable phase to a dispensable phase; (b) a push composition that imbibes fluid and expands, whereby the push composition pushes the calcium channel blocker drug composition from the dosage form; (c) a wall that surrounds the drug and push compositions, said wall comprising a semi-permeable cellulose polymer composition permeable to the passage of fluid present in the environment of use, and a different cellulose polymer comprising a 8,500 to 4,000,000 molecular weight for slowing the rate of fluid passage through the semi-permeable cellulose polymer composition of the wall; (d) at least one exit means in the wall for delivering the drug from the dosage form; and wherein the dosage form is characterized by: (e) a subcoat for the delayed-delivery of drug, which subcoat comprises a hydroxyalkylcellulose polymer possessing a 8,500 to 4,000,000 molecular weight that surrounds the drug and push composition and is positioned between the inside surface of the wall and the drug and push composition; and characterized further by: (f) a delayed-delivery of 30 minutes to 7 hours is provided by (1) the polymer in the drug composition, (2) the polymer in the wall composition and (3) the polymer in the subcoat operating in conjunction, whereby through the combined operations of (1), (2) and (3) a delayed-delivery of the calcium channel blocker drug is provided by the dosage form.
U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338 all relate generally to dosage forms for the controlled drug delivery of a drug, wherein osmotic pressure is employed as the driving force to generate a constant release of the drug from the dosage form provided a constant osmotic pressure is maintained. The dosage forms comprise a semi-permeable membrane, permeable to the passage of exterior fluid and substantially impermeable to the passage of drug, the semi-permeable membrane surrounding and forming a compartment comprising a drug layer and an osmotic layer and, at least one preformed passageway in the membrane communicating with the drug layer in the compartment and the exterior of the dosage form. Typical materials for forming the semi-permeable membrane are cellulose esters, cellulose ethers and cellulose ester-ethers. When the dosage form is exposed to water or any fluid in the body, water is imbibed into the dosage form in a tendency towards osmotic equilibrium due to the osmotic pressure difference. The volume flow rate of water into the dosage form is determined by the osmotic pressure gradient across the membrane and the permeability, area and thickness of the membrane. The drug is pumped out of the dosage form through the orifice at a controlled rate, the rate of which is determined by the volume flow rate of water into the dosage form and the concentration of the drug inside the dosage form.
The Covera-HS(trademark) tablet formulation, which is based on the teachings of U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338, is a controlled onset sustained release drug delivery system designed for bedtime dosing, incorporating a 4 to 5-hour delay in drug delivery. The Covera-HS(trademark) tablet formulation initiates the release of verapamil hydrochloride 4 to 5 hours after ingestion and results in a maximum plasma concentration (Cmax) of verapamil hydrochloride in the morning hours. The delay is introduced by a layer between the active drug core and the outer semi-permeable membrane. As water from the gastrointestinal tract enters the tablet, the delay coating is solubilized and released. As tablet hydration continues, the osmotic layer expands and pushes against the drug layer, releasing verapamil hydrochloride through precision laser drilled orifices in the outer membrane at a constant rate. This controlled rate of drug delivery in the gastrointestinal lumen is independent of posture, pH, and gastrointestinal motility in fed or fasting conditions. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.
The formulations disclosed in U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338 and thus the currently marketed Covera-HS(trademark) tablet formulation, has several limitations. The semi-permeable membrane that surrounds the drug and push compositions is permeable to the passage of the external fluid but is substantially impermeable to the passage of the drug. Delivery of the drug is purported to be essentially constant. However, the release rate of the drug from the dosage form is constant only until the concentration of the drug inside the dosage form falls below saturation. Thereafter, the osmotic gradient decreases across the membrane and the release rate of the drug from the dosage form gradually declines to zero. As a result, the formulations disclosed in U.S. Pat. Nos. 5,160,744; 5,190,765; and 5,252,338 and thus the currently marketed Covera-HS(trademark) tablet formulation does not reliably release verapamil at a sustained rate. As well, upon ingestion, the semi-permeable membrane maintains its physical and chemical integrity during gastrointestinal transit and is eliminated in the feces as an insoluble shell. The osmotically active agents may lack the ability to imbibe sufficient fluid for the maximum self-expansion needed for urging all of the drug from the dosage form. Therefore, due to the nature of the osmotic drug delivery system, some of the drug remains in the insoluble, inflexible shell and is thus not available for the desired absorption and effect. In addition, the formulations may be manufactured with solvents (used to dissolve cellulose ester polymers in the semi-permeable membrane) that are not environmentally friendly, expensive and also require expensive manufacturing processes that need explosion proof equipment and laser guns to drill holes on the surface of the dosage forms. Furthermore, these processes may be unhealthy and may even be harmful to the employees involved in manufacturing these products. The residual solvents remaining in these products may also cause adverse side effects among users of these products.
It is accordingly one object of the present invention to provide a novel and improved pharmaceutical composition for delivering an active ingredient or a plurality of active ingredients from the pharmaceutical composition at a sustained rate after a desired time delay or a controlled onset of release while avoiding the disadvantages of the prior art compositions.
It is a further object of the present invention is to provide pharmaceutical compositions that begin to release active ingredients from the pharmaceutical compositions at a predetermined time delay or controlled onset after administration of the pharmaceutical compositions and which continue releasing the same active ingredients from the pharmaceutical compositions at a predetermined release rate such that the blood levels achieved by such pharmaceutical compositions provide a significant therapeutic benefit to patients suffering from various disease states.
It is yet another object of the present invention to provide a method for administering active ingredients to a patient in need of therapy by administering a pharmaceutical composition which provides a time delay of between about 30 minutes to 6 hours in the delivery of the active ingredient.
It is yet another object of the present invention to provide a method for producing a delayed therapeutic effect of between about 30 minutes to 6 hours in a patient in need of therapy.
It is yet another object of the present invention to provide a method of preparing a pharmaceutical composition for controlled onset and sustained release of an active ingredient.
It is yet another object of the present invention to provide a pharmaceutical composition that delivers an active ingredient selected from the group consisting of very soluble active ingredients, freely soluble active ingredients, soluble active ingredients, sparingly soluble active ingredients, slightly soluble active ingredients, very slightly soluble active ingredients and practically insoluble, or insoluble active ingredients in a controlled and sustained rate to a patient in need of therapy with a controlled onset of between about 30 minutes and 6 hours.
It is yet another object of the present invention to provide a pharmaceutical composition that delivers glipizide (insoluble drug) in a controlled and sustained rate to a patient in need of glipizide therapy with a controlled onset of about 2 hours.
It is yet another object of the present invention to provide a pharmaceutical composition that delivers verapamil HCl (soluble drug) in a controlled and sustained release rate to a patient in need of verapamil therapy with a controlled onset of about 2 hours.
Further and other objects of the invention will become apparent to those skilled in the art from reading the following summary of the invention and the preferred embodiments described and illustrated herein.
In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and
(ii) a functional coating membrane surrounding said core.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a functional coating membrane surrounding said core; and
(iii) a top coating membrane surrounding said functional coating membrane.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core; and
(iii) a functional coating membrane surrounding said seal coating membrane.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane, and
(iv) a top coating membrane surrounding said functional coating membrane.
In an embodiment of the present invention, the active ingredient in the core is dispersed as a solid in a matrix comprising the hydrophilic carrier, the hydrodynamic diffusion enhancer, and the optional conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof.
In an embodiment of the present invention, the core is in a form selected from the group consisting of a tablet, a caplet, a sphere, a spheroid, a granule, a pellet or the like, which form allows for coating.
In an embodiment of the present invention, the pharmaceutical composition is a finished dosage form selected from the group consisting of a tablet, a caplet, a capsule, a sphere, a spheroid, a pellet, a troche, a cachet, a pill or the like in all sizes, shapes and colours.
In an embodiment of the present invention, the core is developed such that the release rate of the active ingredient from the uncoated core is faster than the release rate of the active ingredient from the finished dosage form (coated core). The ratio of hydrophilic carrier to hydrodynamic diffusion enhancer and to the optional conventional pharmaceutically acceptable excipients is optimized to obtain the desired release rate of the active ingredient from the core.
In an embodiment of the present invention, the active ingredient is any ingredient that provides a significant therapeutic benefit to humans or animals when released from the pharmaceutical compositions in a controlled onset and sustained release profile.
Preferably, the active ingredients which are suitable for use in the pharmaceutical compositions of the present invention are selected from the group consisting of very soluble drugs, freely soluble drugs, soluble drugs, sparingly soluble drugs, slightly soluble drugs, very slightly soluble drugs and practically insoluble, or insoluble drugs. According to Remington: The Science and Practice of Pharmacy, 19th Edition, ed. Alfonso R. Gennaro, Vol. 1, Table 1, p. 195, Mack Publishing Company, Easton, Pa. 18042, the above-mentioned descriptive terms for solubility are defined. Specifically, very soluble means that less than 1 part of solvent is required to dissolve 1 part of solute. Freely soluble means that from 1 to 10 parts of solvent are required to dissolve 1 part of solute. Soluble means that from 10 to 30 parts of solvent are required to dissolve 1 part of solute. Sparingly soluble means that from 30 to 100 parts of solvent are required to dissolve one part of solute. Slightly soluble means that from 100 to 1000 parts of solvent are required to dissolve one part of solute. Very slightly soluble means that from 1000 to 10,000 parts of solvent are required to dissolve 1 part of solute. Practically insoluble, or insoluble means that more than 10,000 parts of solvent are required to dissolve 1 part of solute.
Preferably, the active ingredients which are suitable for use in the pharmaceutical compositions of the present invention are selected from the group consisting of anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, oxaprozin, prednisone and prednisolone; coronary dilator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral vasodilator drugs such as naftidrofuryl oxalate, cyclandelate and nicotinic acid; anti-infective drugs such as erythromycin, cephalexin, naldixic acid, clarithromycin, cefuroxime, cefaclor, cefprozil, zidovudine, acyclovir, ofloxacin, ciprofloxacillin, azithromycin and flucloxacillin sodium; psychotropic and/or an antianxiety drugs such as fluazepam, diazepam, amitryptaline, doxepine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipremine, clorazepate, estazolam, lorazepam, alprazolam, bupropion, fluoxetine, buspirone, clonazepam, sertaline, zolpidem, desmethylimipramine, lithium carbonate, lithium sulfate and methylphenidate; central stimulant drugs such as isoproterinol, amphetamine sulphate and amphetamine hydrochloride; antihistamine drugs such as chlorpheniramine, bropheniramine, fexofenadine, loratidine and diphenhydramine; laxative and/or antidiarrheal drugs such as bisacodyl, magnesium hydroxide, loperamide, diphenoxylate, and dioctyl sodium sulfosuccinate; decongestant drugs such as phenylpropanolamine and pseudoephedrine; vitamin substances such as alphatocopherol, thiamin, pyridoxine and ascorbic acid; antacids such as aluminum trisilicate, aluminum hydroxide, cimetidine, ranitidine, famotidine, omeprazole and nizatidine; gastrointestinal sedatives such as propantheline bromide and metoclorpramide; cerebral vasodilators such as soloctidilum, naftidrofuryl oxalate, co-dergocrine mesylate, papaverine and pentoxifylline; anti-anginal drugs such as isosorbide dinitrate, pentaerythritol tetranitrate, verapamil, nifedipine, diltiazem, and glyceryl trinitrate; antiarrythmics such as verapamil, nifedipine, diltiazem, disopyramide, bretylium tosylate, quinidine sulfate, quinidine gluconate and procainamide; antihypertensives such as methyldopa, captopril, hydralazine, propranolol, labetalol, sotalol, terazosin, enalapril, lisinopril, quinalapril, benazepril, ramipril, clonidine, fosinopril, felodipine, immodipine and amlodipine; vasoconstrictors such as ergotamine; substances which influences blood coagulability such as protamine sulfate and epsilon aminocaproic acid; hypnotics such as dichloral phenazone, nitrazepam and temazepam; antinauseants such as chlorpromazine and promethazine theoclate; anticonvulsants such as sodium valproate, phenytoin sodium, divalproex sodium and carbamezipine; neuromuscular drugs such as dentrolene sodium; hypoglycemic agents such as diabenese, insulin, glyburide, glipizide and troglitazone; drugs used in treating thyroid gland disorders such as thyroxin, triiodothyronine and propylthiouracil; diuretics such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone, triampterene and indapamide; uterine relaxant medications such as ritodrine; appetite suppressants such as asphenteramine, diethylproprion hydrochloride and fenfluramine hydrochloride; erythropoietic substances such as folic acid, calcium gluconate and ferrous sulphate; antiasthmatic drugs such as aminophylline, theophylline, orciprenaline sulphate, terbutaline sulphate, albuterol and salbutamol; expectorants such as carbocisteine and guaiphenesin; cough suppressants such as noscapine, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone and dextromethorphan; antiuricemic drugs such as allopurinol, probenecid and sulphinpyrazone; antiseptics such as cetylpyridinium chloride, tyrothricin and chlorhexidine; antilipidimic or anticholesterol agents such as lovastatin, gemfibrozil, simvastatin and pravastatin; pharmaceutically acceptable salts thereof and combinations thereof. Any active ingredient from a very soluble drug to a practically insoluble or insoluble drug would be a suitable active ingredient for the present invention and the active ingredients discussed above are used as examples only.
In an embodiment of the present invention, the hydrophilic carrier is one or more hydrophilic polymeric excipients in any desired ratio to provide a desired release profile of the active ingredient from the pharmaceutical composition.
Preferably, the hydrophilic carrier is a homopolysaccharide or a heteropolysaccharide, preferably selected from the group consisting of xanthan gum, locust bean gum, propylene glycol ester, galactomannan, glucomannan, guar gum, gum acacia, gum tragacanth, alkali metal carageenates, alginates, cellulose alkyl carboxylates, carboxymethyl cellulose, carboxyethyl cellulose, alkali metal salts of cellulose alkyl carboxylates, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxypropyl methylcelluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, polyethylene glycols and polyethylene oxides, gellan gum, alginate salts, natural polysaccharides, gum arabica, etc. and combinations thereof. Some examples of polyethylene glycols and polyethylene oxides commercially available are those under the tradename Polyox(copyright) (Union Carbide, Danbury, Conn.). Any polymeric material that can hydrate and gel in the presence of water would be a suitable hydrophilic carrier for the pharmaceutical compositions of the present invention.
Preferably, the hydrophilic carrier is hydroxypropyl methylcellulose, preferably having a viscosity between about 5 cps and 100,000 cps, a hydroxypropoxyl content between about 7 and 12%, a methoxyl content between about 19 and 30%.
The molecular weight of the hydrophilic carrier is selected based on the solubility of the active ingredient. Low molecular weight grade hydrophilic carriers are utilized for insoluble drug substances. High molecular weight grade hydrophilic carriers are utilized for soluble drug substances. Preferably, a blend of low and high molecular weight hydrophilic carriers are selected such that any desired molecular weight can be accomplished by adjusting the ratio of the blend.
In another embodiment of the present invention, the hydrophilic carrier is a blend of hydroxypropyl methylcelluloses having different molecular weights and/or viscosities.
Preferably, the ratio of the blend of hydroxypropyl methylcelluloses can vary from 1:99 to 99:1 with respect to low and higher molecular weight of hydroxypropyl methylcelluloses.
Preferably, the hydrophilic carrier in said core is present in a concentration of about 5 to 99% W/W of the weight of the core.
In an embodiment of the present invention, the hydrodynamic diffusion enhancer is a substance which has the inherent capability of drawing water towards it, thereby increasing the rate at which water diffuses through a membrane, then absorbs this water, and swells and increases its volume and creates an internal hydrodynamic pressure.
Preferably, the hydrodynamic diffusion enhancer is selected from the group consisting of gellan gum, starches, clays, celluloses, cellulose derivatives, alginates, crospovidone (Polyplasdone(copyright) and Polyplasdone(copyright) XL (ISP, Wayne, N.J.)), croscarmellose sodium (Ac-Di-Sol(copyright), FMC Corp., Philadelphia, Pa.), sodium starch glycolate (Explotab(copyright), Penwest, Patterson, N.Y.) and combinations thereof. Any excipient which has the inherent capability of drawing water towards it, thereby increasing the rate at which water diffuses through a membrane, then absorbs this water, and swells and increases its volume and creates an internal hydrodynamic pressure would be capable of functioning as a hydrodynamic diffusion enhancer and thus would be a suitable hydrodynamic diffusion enhancer for the pharmaceutical compositions of the present invention.
Preferably, the hydrodynamic diffusion enhancer in said core is present in a concentration of about 5 to 60% W/W of the weight of the core.
In an embodiment of the present invention, the binders are substances which can be used to granulate powders that may not otherwise have adequate flowability characteristics required for the tabletting process.
Preferably, the fillers and binders are each selected from the group consisting of polyethylene glycols, microcrystalline cellulose, lactose, starches, starch derivatives, mannitol, sorbitol, dextrose, sucrose, maltodextrin, celluloses, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or other sugars, polysaccharides and gums, etc. and combinations thereof. Any conventional binder would also be suitable as a binder in the pharmaceutical compositions of the present invention.
Preferably, the fillers in said core are present in a concentration of about 2 to 40% W/W of the weight of the core.
Preferably, the binders in said core are present in a concentration of bout 1 to 10% W/W of the weight of the core.
In an embodiment of the present invention, the lubricants and flow promoters are selected from the group consisting of stearic acid, talc, waxes, stearic acid salts, stearic acid derivatives, sodium stearyl fumarate, corn starch, silica derivatives and combinations thereof.
Preferably, the lubricants in said core are present in a concentration of about 0.25 to 4% W/W of the weight of the core.
In an embodiment of the present invention, the optional seal coating membrane, which is also typically known as a film coat, functions to seal all surface pores and to provide a uniform surface for the next coating step.
Preferably, the optional seal coating membrane is present in a concentration of about 0-5% W/W of the core.
The optional seal coating membrane is obtained by preferably spray coating seal coating dispersions onto the surface of uncoated cores using appropriate coating equipment. Usually these dispersions contain low viscosity hydrophilic polymers such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, and plasticizers such as polyethylene glycol 400. These dispersions are commercially available as Opadry(copyright) Clear and Opadry(copyright) both from Colorcon, West Point, Pa. Similar seal coating dispersions are also available from other suppliers. The seal coating membrane is applied to the surface of an uncoated core to smooth out the surface of the core.
In an embodiment of the present invention, the functional coating membrane is applied on top of the core or on top of the optional seal coating membrane.
Preferably, the functional coating membrane is an aqueous polymeric dispersion comprising dispersed plasticizers, film extenders and diffusion enhancers.
Preferably, the functional coating membrane comprises ethylcellulose as an aqueous dispersion, preferably with appropriate coating ingredients dispersed therein.
Preferably, the ratio of the polymer to film extender in the aqueous polymeric dispersion of the functional coating membrane is from about 0.25-0.75 to 0.99-0.01.
Functional coating membranes are obtained by preferably spraying functional coating dispersions onto the surface of the seal coated cores. However, these functional coating dispersions can also be coated straight onto the surface of the uncoated cores. These functional coating dispersions preferably contain a hydrophobic polymer such as ethyl cellulose, a plasticizer, a film extender/diffusion enhancer, and other excipients such as detackifiers or opacifiers, etc. The hydrophobic polymer is mixed with a film extender/diffusion enhancer to give the hydrophobic polymer some degree of hydrophilicity. The plasticizer is added to reduce the glass transition temperature (Tg) of the polymer so that it can be coalesced at a lower temperature (such as 60xc2x0 C.). The plasticizer also makes the functional coating membrane flexible so that it can stretch to some degree without breaking. Examples of such commercially available aqueous polymeric dispersions suitable for use in the present invention are Surelease(copyright) (Colorcon, West Point, Pa.) and Aquacoat(copyright) (FMC Corp, Philadelphia, Pa.). The plasticizers and film extender/diffusion enhancers are dispersed into the commercially available functional coating dispersions such as Aquacoat(copyright) or Surelease(copyright) and then sprayed onto the surface of the uncoated or seal coated cores. Other functional coating dispersions preferably contain acrylic methacrylic copolymers. Examples of such functional coating dispersions commercially available are Eudragit(copyright) (Rohm Pharma GmbH, Weiterstadt, Germany). Aqueous polymeric dispersions containing acrylic methacrylic copolymers, cellulose acetate and other cellulose derivative polymers can be formulated in to aqueous polymers and used for the same purpose. Similar functional coating dispersions can be prepared with other hydrophilic or lyophilize polymers which would be suitable for this purpose.
Preferably, the functional coating membrane is present in a concentration of about 1-25% W/W of the weight of the core.
In an embodiment of the present invention, the optional top coating membrane allows the functional coating membrane to be coalesced.
Preferably, the optional top coating membrane is an aqueous coating dispersion, and preferably the aqueous coating dispersion is present in a concentration of about 0-5% W/W of the core.
Preferably, the aqueous coating dispersion of the optional top coating membrane further comprises dispersed colours.
The aqueous dispersion of the optional top coating membrane may contain any desirable color to color the tablets.
The optional top coating membrane is obtained by preferably spraying top coating dispersions onto the surface of the functional coating membrane. These top coating dispersions are commercially available as Opadry(copyright) white or Opadry(copyright) red, etc., named after the colorant present in the dispersion. Other equivalent brands of functional coating dispersions commercially available in the market are also suitable.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and
(ii) a functional coating membrane surrounding said core.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a functional coating membrane surrounding said core; and
(iii) a top coating membrane surrounding said functional coating membrane.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core; and
(iii) a functional coating membrane surrounding said seal coating membrane.
In accordance with a further aspect of the present invention, there is provided a method for administering an active ingredient to a patient in need of therapy, which method comprises:
administering a pharmaceutical composition to the patient, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane, and
(iv) a top coating membrane surrounding said functional coating membrane.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and
(ii) a functional coating membrane surrounding said core;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a functional coating membrane surrounding said core; and
(iii) a top coating membrane surrounding said functional coating membrane;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core; and
(iii) a functional coating membrane surrounding said seal coating membrane;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for producing a delayed therapeutic effect of 30 minutes to 6 hours in a patient in need of therapy, wherein the method comprises:
(A) administering to the patient a pharmaceutical composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and optionally
(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane, and
(iv) a top coating membrane surrounding said functional coating membrane;
(B) imbibing and/or diffusing fluid into the pharmaceutical composition to provide a delayed delivery of the active ingredient of 30 minutes to 6 hours by the functional coating membrane; and
(C) administering the active ingredient at a delayed time to the patient in need of therapy.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants; and
(ii) a functional coating membrane surrounding said core wherein the method comprises:
(iii) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(iv) granulating the blend with a binder to obtain a wet mass;
(v) drying the wet mass at 60xc2x0 C. for 3 hours;
(vi) lubricating the granules with a lubricant;
(vii) compressing the lubricated granules to form a core;
(viii) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the core;
(ix) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;
(ii) a functional coating membrane surrounding said seal coating membrane; and
(iii) a top coating membrane surrounding said functional coating membrane, wherein the method comprises:
(iv) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(v) granulating the blend with a binder to obtain a wet mass;
(vi) drying the wet mass at 60xc2x0 C. for 3 hours;
(vii) lubricating the granules with a lubricant;
(viii) compressing the lubricated granules to form a core;
(ix) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the core;
(x) applying a top coating membrane with aqueous coating dispersions to the surface of the functional coating membrane; and
(xi) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane; wherein the method comprises:
(iv) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(v) granulating the blend with a binder to obtain a wet mass;
(vi) drying the wet mass at 60xc2x0 C. for 3 hours;
(vii) lubricating the granules with a lubricant;
(viii) compressing the lubricated granules to form a core;
(ix) applying a seal coating membrane to the surface of the core to smooth out the surface;
(x) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the seal coating membrane;
(xi) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:
(i) a core comprising:
(a) an active ingredient;
(b) a hydrophilic carrier;
(c) a hydrodynamic diffusion enhancer; and
(d) optionally conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;
(ii) a seal coating membrane surrounding said core;
(iii) a functional coating membrane surrounding said seal coating membrane; and
(iv) a top coating membrane surrounding said functional coating membrane, wherein the method comprises:
(v) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;
(vi) granulating the blend with a binder to obtain a wet mass;
(vii) drying the wet mass at 60xc2x0 C. for 3 hours;
(viii) lubricating the granules with a lubricant;
(ix) compressing the lubricated granules to form a core;
(x) applying a seal coating membrane to the surface of the core to smooth out the surface;
(xi) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the seal coating membrane;
(xii) applying a top coating membrane with aqueous coating dispersions to the surface of the functional coating membrane; and
(xiii) curing of the coated core at a temperature range of 30xc2x0 C.-80xc2x0 C. for up to 12 hours.
In accordance with a further aspect of the present invention, there is provided a method for controlling the duration of the time delay before which the active ingredient is released from the pharmaceutical composition and the duration of release of the active ingredient(s) after such time delay.
The present invention provides pharmaceutical compositions that contain many ingredients which perform many functions. It is the combination of some or all of these ingredients in the pharmaceutical compositions of the present invention that release the desired active ingredient from the pharmaceutical composition with the desired release profile.
The mechanism of release of the controlled onset sustained release pharmaceutical compositions of the present invention described above is as follows:
1) As the dosage form comes into contact with the gastrointestinal fluids, the optional top coating membrane, when present, hydrates and erodes, thus exposing the functional coating membrane to the environment of the gastrointestinal tract. With time, the gastrointestinal fluids hydrate the film extender/diffusion enhancer in the functional coating membrane and create channels which penetrate the functional coating membrane of the dosage form, thus exposing the optional seal coating membrane to the gastrointestinal fluids. The amount of functional coating membrane applied to the core and the ratio of the polymer to film extender/diffusion enhancer in the functional coating membrane may be adjusted to control the rate at which the gastrointestinal fluids penetrate the functional coating membrane. The optional seal coating membrane, when present, hydrates and erodes, thus exposing the core to the gastrointestinal fluids.
2) The hydrodynamic diffusion enhancer in the core promotes the entry of the gastrointestinal fluids into the core by working as a sponge inside the core. When the required amount of gastrointestinal fluid enters the core, the hydrodynamic diffusion enhancer hydrates and begins to swell. The hydrophilic carrier also hydrates and swells during this time and contributes to the hydrodynamic swelling force provided by the hydrodynamic diffusion enhancer. The ratio of the amount of hydrophilic carrier to hydrodynamic diffusion enhancer can be adjusted to control the extent and degree of swelling by the core. The active ingredient also comes into contact with the gastrointestinal fluids and starts to dissolve. While the hydrodynamic diffusion enhancer and the hydrophilic carrier are swelling inside the core, the functional coating membrane surrounding the core prevents release of the active ingredient, resulting in a time delay in the onset of release of the active ingredient from the dosage form. The predetermined time delay can be varied from between about 30 minutes to 6 hours.
3) Upon further swelling, the core stretches and expands the functional coating membrane surrounding the core and helps the active ingredient to permeate through the functional coating membrane and pass out of the dosage form. The rate at which the active ingredient can diffuse out of the dosage form is controlled by the composition of the core and the composition and amount of the functional coating membrane applied to the core. The amount of hydrodynamic diffusion enhancer in the core may be adjusted such that the hydrodynamic swelling force generated by this material and the time required to generate this force are adequate to stretch and expand the functional coating membrane by the end of the required time delay in order to facilitate the release of the active ingredient from the dosage form.
4) Depending upon the composition of the core and the amount of the functional coating membrane applied to the core, the swelling core may generate adequate hydrodynamic swelling force to eventually rupture the functional coating membrane. If and when the functional coating membrane ruptures, it ruptures around the edges of the dosage form. Rupturing in this way may leave the functional coating membrane on the upper and the bottom surfaces of the dosage form intact for an extended period of time. The remaining intact functional coating membrane together with the fully hydrated core control the release of the active ingredient from the dosage form in a substantially zero order fashion for the desired period of time. The release of the active ingredient from the dosage form after the programmed time delay can be varied from a substantially zero order rate of release to a substantially first order rate of release. The sustained release of the active ingredient from the dosage form can be adjusted from between about 6 to 24 hours post the initial programmed time delay.
The pharmaceutical compositions of the present invention have several advantages. The present invention enables persons skilled in the art to manufacture controlled onset and sustained release pharmaceutical compositions using mostly aqueous dispersions and using conventional equipment which are used by most pharmaceutical companies. Thus, the pharmaceutical compositions disclosed in the present invention are essential to deliver active ingredients to humans or animals in an environmentally friendly form, with all of the desired functionality of controlled onset and sustained release, with no risk of adverse side effects from residual solvents.
The controlled onset feature of the present pharmaceutical compositions provide for: a) release of the active ingredient at specific locations along the gastrointestinal tract, or b) colonic release of the active ingredient or c) protection of the stomach from any damage the active ingredient may cause or d) facilitation of high levels of the active ingredient in the blood during any desired time period during the day or night such as, early morning hours to provide maximum protection against heart attacks, or e) the treatment of diseases that occur only in certain portions of the gastrointestinal tract such as ulcerative colitis in the colon, etc.
The sustained release feature of the present pharmaceutical compositions are extremely useful in providing uniform blood levels of active ingredients to obtain a more consistent pharmacological response, reduce peak to trough ratios and thereby reduce the incidence and/or severity of side effects, improve patient compliance, reduce the cost of overall treatment, etc.
Thus, combining both the features of controlled onset and sustained release into a single pharmaceutical composition along with using environmentally friendly manufacturing processes that do not use ozone depleting solvents and/or carcinogenic solvents to produce such a pharmaceutical composition and using conventional manufacturing equipment, the pharmaceutical compositions of the present invention are a significant advancement over the current state of art technology (prior art).